The antiphospholipid syndrome (APS) is a life-threatening thrombotic disorder characterized by a spectrum of autoantibodies that interfere with blood clotting. Recent evidence suggests that minor genetic variations in coagulation proteins may affect the likelihood for thrombosis in APS patients, either by an indirect, additive risk, or by altering the function of target proteins in a way that affects autoantibody incidence or pathogenicity. This application proposes: Aim 1: To determine if combined, common variants of specific candidate genes associate with APS. A TDT analysis of 1,000 APS patients and their parents will be performed, examining strategic single nucleotide polymorphisms in three interacting coagulation proteins known to be implicated in APS pathology: 1.) the anticoagulant, protein S 2.) its plasma inhibitor, C4b Binding Protein (C4BP) 3.) beta 2-glycoprotein I, a major APS antigen which also may regulate protein S. Aim 2: To produce functional, recombinant protein S, beta 2-glycoprotein I and C4BP domains (both wild-type and polymorphic) in an insect cell system and to compare each in binding interactions with the others, and in their effects on protein S function in vitro. Aim 3: To evaluate individual APS plasma for the decreased free protein S which is known to be prevalent in these patients and to correlate this with presence or absence of candidate polymorphisms and with antibody specificities for the recombinant wild type or polymorphic domains. Single or combined genetic factors may determine the tertiary structures and strength of interactions between several, key protein targets of APS antibodies. Determining the impact of common polymorphisms on the occurrence and/or pathogenicity of autoantibodies could lead to improved diagnostic tests and/or novel, mechanism-based treatments for APS. Additionally, the study of differences in interactions between these coagulation proteins conferred by common, inherited polymorphisms will have intrinsic value, not limited to the antiphospholipid syndrome.